PROJECT SUMMARY At the end of 2018, the United Nations estimated that 38 million people were living with HIV/AIDS with 1.7 million new infections. Although a prophylactic vaccine would do much to halt this epidemic, attaining durable remission among HIV-1 infected individuals would not only curb new infections but also dramatically reduce the societal burden required to maintain continuous life-long ART treatment for so many. Unfortunately, cellular therapeutic interventions to purge HIV-1 infected cells in vivo are relatively limited. MHC-E-restricted CD8+ T cells may represent a universally applicable therapeutic approach. With only two nearly identical HLA-E alleles expressed in the majority of the human population, MHC-E-restricted HIV-specific T cell receptors could be utilized as a donor unrestricted therapeutic reagent. Strain 68-1 RhCMV vectors encoding SIV antigens (RhCMV/SIV) are capable of stringently controlling SIV replication, and that protection is dependent on the induction of SIV-specific MHC-E-restricted CD8+ T cells. Despite its prophylactic utility, RhCMV induces an effector memory CD8+ T cell response directed at portals of HIV/SIV entry not secondary lymphoid tissues where the bulk of SIV resides during chronic infection. Prior studies have demonstrated that CD8+ T cells transduced with CXCR5 traffic to the lymph node B-cell follicle a key site of the SIV/HIV reservoir. In this proposal, we will sequence full length MHC- E-restricted T cell receptors from RhCMV/SIV vaccinated macaques that stringently controlled SIV replication. We will generate autologous CD8+ T cell transductants expressing these MHC-E-TCR and CXCR5 and infuse them into SIV-infected ART-suppressed rhesus macaque. After release of ART, we will use a combination of tissue staining and single-cell RNA sequencing to assess whether these transductants traffic to the B-cell follicle and activate in response to infected virus-producing cells. In addition, we will assess whether MHC-E-TCR transductants delay viral rebound. The experiments outlined in this project may form the basis of a new alternative universal therapeutic intervention for those infected with HIV-1.